Stroke is the third leading cause of death and the leading cause of adult disability in developed countries. In the United States, approximately 795,000 people experience a new or recurrent each year. See, e.g., Lloyd-Jones et al., Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121:948-954; 2010. Intravenous thrombolysis with tissue plasminogen activator (tPA) remains the only FDA-approved therapy for acute ischemic stroke. At present, only a small fraction of potentially eligible stroke patients in the United States are receiving tPA therapy, and it is estimated that the rate of tPA use is 1.8% to 2.1% of all ischemic stroke patients. See e.g., Kleindorfer et al., US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate, Stroke 39:924-928; 2008. One barrier to wide-spread implementation of acute stroke thrombolysis is the fear of symptomatic intracerebral hemorrhage (ICH). See, Tanne et al., Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice; the Multicenter rt-PA Stroke Survey. Circulation 105:1679-1685; 2002. Evidence from randomized clinical trials and subsequent clinical experience clearly demonstrates that tPA thrombolysis presents real safety concerns due to a 10-fold increase to the incidence of symptomatic ICH and a 50% mortality rate in stroke patients who have such bleeding. See, e.g., NINDS. The NINDS t-PA Stroke Study Group, Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 28:2109-2118; 1997; Lapchak, P. A. Hemorrhage transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep 2:38-43; 2002; and Carpenter, C. R. et al., Thrombolytic Therapy for Acute Ischemic Stroke beyond Three Hours. J Emerg Med:doi:10.1016/j.jmermed.2010.1005.1009; 2010.
There has been an urgent need to identify early diagnostic indicators to exclude “eligible patients” (within the 3-hr thrombolytic time window) at high risk of ICH and to include “non-eligible patients” (beyond the 3-hr limit, but still presenting salvageable penumbral tissue, but at low risk of ICH) for tPA treatment, thus allowing more stroke patients to benefit from tPA treatment. Unfortunately, there are currently no such early indicators for ICH available to guide tPA thrombolysis in clinical practice.
Blood brain barrier (BBB) disruption is a hypothesized precursor to ICH and the timing of BBB damage is early enough to be within the thrombolytic time window. See, Warach, S. et al., Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 35:2659-2661; 2004; and Hacke, W. et al., Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359:1317-1329; 2008.
Using advanced permeability MRI techniques, a causal predictive relationship between early ischemic BBB damage and tPA-associated ICH has been supported by animal and human stroke studies. See NINDS and Warach et al, cited above, as well as Knight, R. A. et al., Prediction of impending hemorrhagic transformation in ischemic stroke using magnetic resonance imaging in rats. Stroke 29:144-151; 1998; Sun, L. et al., Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia. J. Cereb. Blood Flow Metab; Kassner, A. et al., Recombinant tissue plasminogen activator increases blood-brain barrier disruption in acute ischemic stroke; an MR imaging permeability study, AJNR Am J Neuroradiol 30:1864-1869; 2009; and Hjort, N. et al., MRI detection of early blood-brain barrier disruption: parenchymal enhancement predicts focal hemorrhagic transformation after thrombolysis. Stroke 39:1025-1028; 2008. The studies all showed an intriguing phenomenon that ischemic brain regions with compromised BBB at the time of tPA administration are at high risk of intracerebral bleeding at later times during thrombolytic reperfusion. As thus, early ischemic BBB damage appears to be a key factor to determine whether ischemic brain tissue can safely withstand a return of blood flow and is increasingly considered a promising pretreatment predictor for post-thrombolysis ICH. Currently, great efforts have been made to develop a BBB damage-based MRI signature to predict post-thrombolysis ICH and these efforts have achieved substantial progress. However, it may not be practical to use this MRI signature as an early indicator for ICH because quantitative MRI measurement for BBB permeability takes time (at least 1 hr or longer), which in acute stroke care, every minute counts as ischemic brain tissue dies fast. In addition, limited access, high cost and low sensitivity are added concerns to MRI measurement. In contrast, a rapid and reliable blood-test based indicator for early ischemic BBB damage would be an ideal predictor of post-thrombolysis ICH. In addition to helping triage stroke patients for thrombolytic therapy, a biomarker for early BBB damage may help guide the delivery of neuroprotectants to the brain to reap their maximum benefit because most neuroprotectants cannot cross the BBB or are incapable of timely reaching their desired sites of action. Early BBB damage is also a common event contributing to brain injury and worse outcome in patients with traumatic brain injury, thus a quick diagnostic biomarker of BBB damage may also help improve the management of traumatic brain injury.